DNA Repair in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Abstract

Acute myeloid leukemia (AML) comprises approximately 25% of all leukemias in adults in the western world. It is a clonal disorder caused by uncontrolled proliferation and accumulation of myeloid progenitor cells in the bone marrow with impaired differentiation, leading ultimately to hematopoietic failure. Myelodysplastic syndrome (MDS) is characterized by persistent pancytopenia, dysplastic hematopoesis in bone marrow, increase in blast cell number and high risk of progression to AML. MDS is a disease of elderly, which makes treatment difficult (Estey 2008). The median age of AML patients is also high and is estimated to be 66 to 70 years. Standard therapeutic strategies in MDS and AML depend on various factors, of which age, comorbidities and performance status are most important. Treatment modalities vary from the best supportive care through low dose chemotherapy to intensive dose chemotherapy and allogeneic bone marrow transplantation (Robak T, Wierzbowska A 2009). Untreated MDS and AML carry extremely poor prognosis with high mortality. The search for new drugs in AML and MDS is stimulated by the significant progress in the understanding of the biology of both diseases. Abnormal myeloid cells usually carry chromosomal anomalies, including translocations, deletions, and allelic loss. Typical cytogenetic changes seen in AML are balanced translocations such as t(8,21), t(15,17) which result in formation of a fusion gene. MDS is characterized by deletions of fragments or whole chromosomes hence loss of genetic information. DNA methylation dysregulation is one of the postulated mechanisms of leukemia development and progression. Hypermethylation of DNA generally results in a decreased expression of tumor suppressor genes and defective cell cycle control and is a hallmark of MDS and AML. Epigenetic changes augment genetic alterations occurring in cancer cells and promote tumor progression. Several sequential events in the genom are required to create a leukemic clone. Defects of DNA repair are the key mechanism of development and progression of myeloid leukemias. Most of the AML cases originate de novo, but around 10 to 20% of patients have previous exposure to myelotoxic substances. Preceding anticancer treatment or exposure to chemical toxins may result in severe damage to DNA and in case of defective DNA repair mechanisms lead to secondary AML. DNA repair mechanisms may influence not only the risk of leukemia development, but also its refractoriness to treatment. Several major pathways of DNA repair exist: Homologous Recombination (HR), Non Homologous End Joining (NHEJ), Base Excision Repair (BER), Nucleotide Excision Repair